The hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide. Following acute HCV infectton, only 15-45% of individuals resolve the virus spontaneously. Clearance of HCV infecfion requires the generation of potent antiviral T cell effectors. Virally encoded proteins are known to induce a dysregulated activation state In peripheral blood monocytes, and cytokines from aberrantly activated monocytes can adversely affect T cell priming by dendritic cells. In preliminary studies, we have shown that polymorphisms of the Killer Immunoglobulin Receptor (KIR) family of NK cell receptors and their human leukocyte antigen (HLA) class I ligands are major host determinants of spontaneous HCV clearance; that acute HCV infection triggers NK cell activation pathways involving the natural cytotoxicity receptor NKG2D; and that stress-inducible cell-surface ligands for NKG2D are expressed on HCVactivated peripheral blood monocytes. We hypothesize that NK cells may promote effective T cell priming by clearing aberrantly-activated monocytes and virally infected cells, or by contribufing to the elaboration of potent antiviral cytokines. Moreover, we propose that effector and cytokine responses of NK cells may be triggered, in part, by NKG2D and modulated by inhibitory and activating KIR, and that NK cells with a